It was traditionally believed that the tumor was the seed that lay in the passive soil of the microenvironment, with the latter providing "permissive elements" for the tumor to grow and invade. Subsequently, it was recognized that both neoplasia and its microenvironment interacted as equal partners. Recent advances addressing genomic alterations in the tumor microenvironment, relevant to clinical outcome and treatment choices, are summarized. These include microenvironmental genomic alterations not only in different solid tumors, but also, rather surprisingly, in inflammatory bowel disease. These observations promise new biomarkers of prognosis and a new compartment to target therapy.